Cellular plasticity and regeneration after radiation damage in Drosophila More than half of cancer patients receive ionizing radiation (IR), alone or as a component of their treatment (www.cancer.org). IR induces DNA damage to kill cells. Surviving cancer cells could, however, regenerate the tumor, leading to treatment failure. While we understand much about how cells repair DNA damage or undergo cell death, how tumors regenerate remains an active area of research with key questions remaining unanswered. Our overall objective is to understand how tissues regenerate after damage by IR in vivo in a multicellular context, to identify and characterize the genes involved in this process, and to develop genetic and chemical tools to manipulate the function of these genes. We have been using Drosophila melanogaster to study regeneration after IR damage because we can perform large-scale gene discovery and molecular genetic analysis, and use precision lineage-tracing to follow specific subsets of regenerative cells over time as they interact with their surroundings. DNA repair, cell death and regeneration in Drosophila share genetic and molecular features with vertebrates. Chemical modulators of IR-induced regeneration we discovered in Drosophila behave similarly in human cancer models. These findings provide proof of concept that what we learn in Drosophila will likely apply to humans. Regeneration of Drosophila larval organs called imaginal discs occurs without a dedicated stem cell pool. We recently identified a previously unknown mode of regeneration in Drosophila larval wing discs, whereby epithelial cells acquire stem cell-like properties. These properties include the ability to change cell fate and translocate to areas of the disc with greater need for cell replenishment. The ability to behave like stem cells, we found, is induced by ionizing radiation (IR) and is limited to specific subsets of cells within the wing disc. IR-induced stem-ness in Drosophila parallels the increasingly appreciated ability of cancer treatments including IR to induce stem cell-like properties in non-stem cancer cells. This project will address the following essential questions. What are the consequences of IR that induce stem cell-like behavior in non-stem cells? Why do some irradiated cells respond by displaying stem cell-like behavior while others do not? What internal and external factors regulate the induction of stem cell-like behavior? Answers to these questions will not only increase our understanding of regeneration after IR damage but also will identify mechanisms that may be modulated to improve treatment outcome in human cancers. !